We propose to conduct a randomized controlled trial (RCT) to compare safety, feasibility and positive predictive value (PPV) of two ovarian cancer screening strategies, one using CA125 and HE4 together as a first-line screen, the other introducing HE4 as a second-line screen. Women aged 35-80 will be eligible if they are at elevated risk based on a documented mutation in BRCA1 or BRCA2 or a pedigree suggestive of inherited susceptibility;800 such women will be enrolled and screened semi-annually. Women aged 50-80 will be eligible if they have elevated risk based on a previously developed OvCaRisk model;400 such women will be enrolled and screened annually. We will interpret serum markers using the previously developed parametric empirical Bayes (PEB) longitudinal algorithm (above a threshold corresponding to 90%, 95% or 99% specificity) to take advantage of rise in a marker as a signal of disease, a phenomenon that has been well documented. We will target a positive predictive value of 10% in both arms, corresponding to a ratio of 10 surgeries per cancer detected. In Aim 1 we will document protocol-indicated surgical procedures and malignancies detected in order to rule out a ratio of surgeries to malignancies greater than 20. In Aim 2 we will document compliance with first- and second-line screens and test the null hypothesis that compliance does not differ between the two arms. In Aim 3 we will document effects on health-related quality of life (HRQOL) and test the null hypotheses that 1) effects on HRQOL do not differ between the two arms and 2) effects on cancer worry do not differ between women who do and do not experience a false-positive first-line screen. Our goal is that the results of this RCT together with results of ongoing large efficacy trials will lead to clinical implementation of screening using novel markers within 5 years. We have partnered with Abbott Diagnostics and the Canary Foundation to accelerate translation. Four clinical centers (Swedish Medical Cancer, Cedars-Sinai, Stanford and City of Hope) will participate, and participation will be offered to all Ovarian SPORE institutions. Data will also support analyses ofthe cost- effectiveness of screening using each strategy, and estimation of the costs of conducting a full-scale efficacy trial should such a trial be required in the future. RELEVANCE (See instructions): This project will introduce HE4 as an early detection and diagnostic marker for the first time in a prospective clinical trial. We will denhonstrate and evaluate better strategies than are currently used for screening high- risk women. Clinical implementation may follow without the need for another large trial, by combining data from this study with reports from ongoing efficacy trials.